N-9,10-dihydrolysergyl-m-aminobenzoic acid amide derivative

ABSTRACT

The present invention provides compounds of formula I, ##STR1## wherein X is hydrogen, chlorine or bromine and 
     Y is hydrogen or bromine, with the proviso that when X is chlorine Y is hydrogen, 
     Z is carbonyl or sulphonyl, 
     R 1  is alkyl of 1 to 4 carbon atoms, and 
     either (i) 
     R 2  is hydrogen or alkyl of 1 to 5 carbon atoms, and 
     R 3  is hydrogen, alkyl of 1 to 5 carbon atoms, or phenyl, 
     or (ii) 
     R 2  together with R 3  is a radical of formula ##STR2## wherein R 4 , R 5 , R 6  and R 7  are, independently, hydrogen or alkyl of 1 to 4 carbon atoms, 
     or (iii) 
     R 2  together with R 4  is a radical of formula 
     
         --(CH.sub.2).sub.2 --A--(CH.sub.2).sub.2 -- 
    
     wherein A is a bond, oxygen, sulphur or NR 8  wherein R 8  is hydrogen, alkyl of 1 to 4 carbon atoms, phenyl or alkoxyphenyl, 
     useful as venotonising agents.

This invention relates to ergot derivatives.

The present invention provides compounds of formula I, ##STR3## whereinX is hydrogen, chlorine or bromine and

Y is hydrogen or bromine, with the proviso that when X is chlorine Y ishydrogen,

Z is carbonyl or sulphonyl,

R₁ is alkyl of 1 to 4 carbon atoms, and

either (i)

R₂ is hydrogen or alkyl of 1 to 5 carbon atoms, and

R₃ is hydrogen, alkyl of 1 to 5 carbon atoms, or phenyl,

or (ii)

R₂ together with R₃ is a radical of formula ##STR4## wherein R₄, R₅, R₆and R₇ are, independently, hydrogen or alkyl of 1 to 4 carbon atoms,

or (iii)

R₂ together with R₃ is a radical of formula

    --(CH.sub.2).sub.2 --A--(CH.sub.2).sub.2 --

wherein A is a bond, oxygen, sulphur or NR₈ wherein R₈ is hydrogen,alkyl of 1 to 4 carbon atoms, phenyl or phenyl monosubstituted by alkoxyof 1 to 4 carbon atoms.

Z is preferably carbonyl.

R₁ is conveniently methyl, or isopropyl or sec-butyl. When X and Y areeach hydrogen and R₂ and/or R₃ are alkyl, then preferably at least oneof R₂ and R₃ is alkyl of 2 or more carbon atoms, e.g. ethyl orisopropyl. When X and Y are each other than hydrogen and R₂ and/or R₃ isalkyl this is conveniently methyl or isopropyl. Preferably R₂ and R₃ arethe same.

Preferably R₄ is the same as R₅, and R₆ is the same as R₇. It is alsopreferred that R₄, R₅, R₆ and R₇ are identical. When R₄, R₅, R₆ and/orR₇ is alkyl, this is preferably methyl or ethyl. A is conveniently agroup NR'₈ wherein R₈ ' is phenyl, alkoxyphenyl or preferably alkyl,especially methyl.

When R₈ is alkoxyphenyl, this is conveniently methoxyphenyl orethoxyphenyl.

Preferably R₂ and R₃ are chosen from hydrogen or alkyl or are together aradical --(CH₂)₂ --A--(CH₂)₂ --.

The present invention provides a process for the production of acompound of formula I as defined above, which comprises condensing areactive functional acid derivative of a compound of formula II,##STR5## Wherein X, Y and R₂ are as defined above, with a compound offormula III, ##STR6## wherein Z, R₂ and R₃ are as defined above.

The process may be effected in conventional manner for the production ofanalogous lysergic acid amides by condensation reactions.

As the reactive functional acid derivative of a compound of formula IImay be used the acid chloride, the acid azide, or a mixed anhydride ofan acid of formula II with sulphuric or trifluoroacetic acid, orpreferably the reaction product of a compound of formula II with oxalylchloride in the presence of dimethylformamide.

The starting materials are known or may be made in conventional manner.

Free base forms of the compounds of formula I may be converted into acidaddition salt forms in conventional manner and vice versa. A suitableacid for salt formation is maleic acid, methanesulphonic acid,phosphoric acid, tartaric acid or hydrochloric acid.

In the following examples all temperatures are in degrees centigrade andare uncorrected.

EXAMPLE 1 N-9,10-dihydrolysergyl-m-aminobenzoic acid diethylamide

12.9 g Oxalyl chloride in 40 ml absolute acetonitrile are added dropwiseover 20 minutes to a mixture of 125 ml absolute dimethylformamide and 75ml absolute acetonitrile cooled to -15° to -20°. After the mixture isstirred for 10 minutes, 40.5 g of 9,10-dihydrolysergic acid are added.The mixture is stirred for a further 1/2 hour at 0° and then cooled to-10° to -15°. 75 ml pyridine and then 19.1 g m-aminobenzoic aciddiethylamide are added. The mixture is stirred for 21/2 hours, pouredonto 300 ml of an aqueous 2 N sodium carbonate solution and extractedthree times with methylene chloride. The combined organic phases afterone washing with aqueous sodium carbonate are evaporated and the residueis quickly chromatographed on aluminium oxide to yield the titlecompound in free base form, m.p. 138°-141° (from saturated aqueous ethylacetate).

Methanesulphonate: 8 g of the base in ethanol are treated with 18 ml 1 Nmethanesulphonic acid in ethanol. The methanesulphonate crystallisesout, is filtered off, washed with ethanol and dried. M.P. 228°-230°(decomp.) [α]_(D) ²⁰ =-72° (c=1, dimethylformamide).

The starting material, m-aminobenzoic acid diethylamide (m.p. 80°-81°)is obtained by treating m-nitrobenzoyl chloride with diethylamine andcatalytically hydrogenating over palladium on charcoal (10% by weightPd) the resultant m-nitrobenzoic acid diethyl amide (m.p. 68°-70°).

In analogous manner to that described in Example 1, the followingcompounds of formula I may be obtained:

    __________________________________________________________________________    Ex.                                                                           No.                                                                              X Y Z     R.sub.1                                                                             R.sub.2                                                                              R.sub.3  M.Pt..sup.1) /[α].sub.D .sup.20                                         11)                                        __________________________________________________________________________    2  H H SO.sub.2                                                                            CH.sub.3                                                                            CH.sub.3                                                                             CH.sub.3 150°-152°.sup.3)                                                /-116°                                                                 (c = 1,02)                                 3  H H CO    CH.sub.3                                                                             ##STR7##       163°-165°.sup.3)                                                /-112° (c = 1,00)                   4  H H CO    CH.sub.3                                                                             ##STR8##       from 82°.sup.4) /-80,2°                                         (c = 1,02)                                 5  H H CO    CH.sub.3                                                                            CH(CH.sub.3).sub.2                                                                   CH(CH.sub.3).sub.2                                                                     274°-276°.sup.3)                                                /-93.4°                                                                (c = 1,04)                                 6  H H SO.sub.2                                                                            CH.sub.3                                                                            CH(CH.sub.3).sub.2                                                                   CH(CH.sub.3).sub.2                                                                     118°-190°.sup.3)                                                /-105°                                                                 (c = 1)                                    7  H H CO    CH.sub.3                                                                            H      CH.sub.3 154°-156°.sup.3)                                                /-85.2°                                                                (c = 1,8).sup.12)                          8  H H CO    CH.sub.3                                                                            CH(CH.sub.3).sub.2                                                                   H        203°-205°.sup.5)                                                /-77.3°                                                                (c = 1,8).sup.12)                          9  H H CO    CH.sub.3                                                                            CH.sub.3                                                                             CH.sub.3 204°-205°.sup.2) 3)                                             /-61.3°                                                                (c = 1).sup.14)                            10 H H CO    CH.sub.3                                                                            CH.sub.3                                                                             C.sub.6 H.sub.5                                                                        185°-188°.sup.3)                                                /-67.2°                                                                (c = 2).sup.12)                            11 Br                                                                              Br                                                                              CO    CH.sub.3                                                                            CH.sub.3                                                                             CH.sub.3 182°-185°.sup.6)                                                /-60,6°                                                                (c = 0.9).sup.13)                          12 Cl                                                                              H CO    CH.sub.3                                                                            CH.sub.3                                                                             CH.sub.3 168°.sup.6) /-101°                                              (c = 0,76)                                 13 Br                                                                              H CO    CH.sub.3                                                                            CH.sub.3                                                                             CH.sub.3 166°-168°.sup.3)                                                /-139°                                                                 (c = 0,99)                                 14 H Br                                                                              CO    CH.sub.3                                                                            CH.sub.3                                                                             CH.sub.3 197°-198°.sup.3) /                                              -90,6°(c = 1.03)                    15 Br                                                                              Br                                                                              CO    CH.sub.3                                                                            CH(CH.sub.3).sub.2                                                                   CH(CH.sub.3).sub.2                                                                     from 230°.sup.7) /                                                     -71.5° (c = 1.0)                    16 Br                                                                              Br                                                                              CO    CH.sub.3                                                                            H      CH.sub.3 290°-292°.sup.2)3) /                                            -102° (c = 1)                       17 Br                                                                              Br                                                                              CO    CH.sub.3                                                                            CH.sub.3                                                                             C.sub.6 H.sub.5                                                                        239°-242°.sup.2) 8) /                                           -121° (c = 2)                       18 Br                                                                              Br                                                                              CO    CH.sub.3                                                                            (CH.sub.3).sub.2(CH.sub.2).sub.3C(CH.sub.3).sub.2                                             208°-210°.sup.2) 3) /                                           -88.3° (c = 1)                      19 Br                                                                              Br                                                                              SO.sub.2                                                                            CH.sub.3                                                                            CH(CH.sub.3).sub.2                                                                   CH(CH.sub.3).sub.2                                                                     275°-277°.sup.5)                                                -82.4° (c = 1)                      20 H H CO    CH(CH.sub.3).sub.2                                                                  CH.sub.3                                                                             CH.sub.3 183°-186°.sup.4) /                                              -113°  (c = 0.93)                   __________________________________________________________________________     .sup.1) M.Pt is decomposition point except where marked                       .sup.3) is free base                                                          .sup.4) is demi tartrate containing per mole 1 mole of                        .sup.5) is methanesulphonate                                                  .sup.6) is hydrogen maleate                                                   .sup.7) is dihydrogen phosphate                                               .sup.8) is hydrochloride                                                      .sup.11) [α].sub.D .sup.20 in pyridine except when marked .sup.12)      in dimethyl formamide or .sup.13) in methanol or .sup.14) in ethanol.    

In analogous manner to that described in formula I the followingcompounds of formula I may be obtained wherein R₁ is ethyl, X and Y areeach hydrogen, Z is SO₂ and NR₂ R₃ is: ##STR9##

The compounds exhibit venoconstricting activity as indicated by standardtests, e.g. by a pressoric effect and a blood pressure rise in thepithed rat on administration of from 0.001 to 1 mg/kg i.v. of thecompounds according to the principles of Gillespie and Muir, Brit. J.Pharmacol. 30, 78-87 (1967).

The compounds are therefore useful as venotonising agents, e.g. for thetreatment of orthostatic hypotension such as postural orthostasis andmigraine.

For this use the dosage will, of course, vary depending on the compoundemployed, mode of administration and treatment desired. However, ingeneral, satisfactory results are obtained when administered at a dailydosage of from about 0.001 mg to about 5 mg per kg animal body weight,conveniently given in divided doses 2 to 4 times a day or in sustainedrelease form. For the larger mammals, the total daily dosage is in therange from about 0.15 to about 150 mg (e.g. from 0.5 to 10 mg), anddosage forms suitable for oral administration comprise from about 0.04to about 75 mg of the compounds admixed with a solid or liquidpharmaceutical carrier or diluent.

The Example 1 compound is the preferred compound.

The compounds of formula I may be administered in pharmaceuticallyacceptable acid addition salt form. Such acid addition salt formsexhibit the same order of activity as the free base forms and arereadily prepared in conventional manner. The present invention alsoprovides a pharmaceutical composition comprising a compound of formulaI, in free base form or in pharmaceutically acceptable acid additionsalt form, in association with a pharmaceutically carrier or diluent.

Such compositions may be in the form of, for example, a solution or atablet.

In a group of compounds R₄, R₅, R₆ and R₇ are identical and each areeither hydrogen or methyl.

In a first group of compounds Z is carbonyl.

In a second group of compounds Z is sulphonyl.

In a third group of compounds R₂ and R₃ are defined as significance (i)stated above with respect to formula I. In a first sub-group R₃ ishydrogen or alkyl. In a second sub-group R₃ is phenyl.

In a fourth group of compounds R₂ and R₃ are defined as significance(ii) stated above with respect to formula I.

In a fifth group of compounds R₂ and R₃ are defined as significance(iii) stated above with respect to formula I. In a first sub-group A isa bond. In a second sub-group A is O. In a third sub-group A is S. In afourth sub-group A is NR₈.

I claim:
 1. A compound of formula I, ##STR10## wherein X is hydrogen,chlorine or bromine andY is hydrogen or bromine, with the proviso thatwhen X is chlorine Y is hydrogen, Z is carbonyl or sulphonyl, R₁ isalkyl of 1 to 4 carbon atoms, andeither (i) R₂ is hydrogen or alkyl of 1to 5 carbon atoms, and R₃ is hydrogen, alkyl of 1 to 5 carbon atoms, orphenyl,or (ii) R₂ together with R₃ is ##STR11## wherein R₄, R₅, R₆ andR₇ are, independently, hydrogen or alkyl of 1 to 4 carbon atoms,or (iii)R₂ together with R₃ is

    --(CH.sub.2).sub.2 --A--(CH.sub.2).sub.2 --

wherein A is a bond,or a pharmaceutically acceptable acid addition saltthereof.
 2. A pharmaceutical composition useful in the treatment oforthostatic hypotension or migraine comprising a therapeuticallyeffective amount of a compound of claim 1 in association with apharmaceutical carrier of diluent.
 3. A method of treating orthostatichypertension or migraine in animals, which comprises administering atherapeutically effective amount of a compound of claim 1, to an animalin need of such treatment.
 4. The compound of claim 1 which isN-9,10-dihydrolysergyl-m-aminobenzoic acid diethylamide.
 5. The compoundaccording to claim 1 in which X, Y, Z, R₁, R₂ and R₃ are H, H, SO₂, CH₃,CH₃, and CH₃ respectively.
 6. The compound according to claim 1 in whichX, Y, Z, R₁, R₂ and R₃ are H, H, CO, CH₃, CH(CH₃)₂ and CH(CH₃)₂respectively.
 7. The compound according to claim 1 in which X, Y, Z, R₁,R₂ and R₃ are H, H, SO₂, CH₃, CH(CH₃)₂ and CH(CH₃)₂ respectively.
 8. Thecompound according to claim 1 in which X, Y, Z, R₁, R₂ and R₃ are H, H,CO, CH₃, H and CH₃ respectively.
 9. The compound according to claim 1 inwhich X, Y, Z, R₁, R₂ and R₃ are H, H, CO, CH₃, CH(CH₃)₂ and Hrespectively.
 10. The compound according to claim 1 in which X, Y, Z,R₁, R₂ and R₃ are H, H, CO, CH₃, CH₃ and CH₃ respectively.
 11. Thecompound according to claim 1 in which X, Y, Z, R₁, R₂ and R₃ are H, H,CO, CH₃, CH₃ and C₆ H₅ respectively.
 12. The compound according to claim1 in which X, Y, Z, R₁, R₂ and R₃ are Br, Br, CO, CH₃, CH₃ and CH₃respectively.
 13. The compound according to claim 1 in which X, Y, Z,R₁, R₂ and R₃ are Cl, H, CO, CH₃, CH₃ and CH₃ respectively.
 14. Thecompound according to claim 1 in which X, Y, Z, R₁, R₂ and R₃ are Br, H,CO, CH₃, CH₃ and CH₃ respectively.
 15. The compound according to claim 1in which X, Y, Z, R₁, R₂ and R₃ are H, Br, CO, CH₃, CH₃ and CH₃respectively.
 16. The compound according to claim 1 in which X, Y, Z,R₁, R₂ and R₃ are Br, Br, CO, CH₃, CH(CH₃)₂ and CH(CH₃)₂ respectively.17. The compound according to claim 1 in which X, Y, Z, R₁, R₂ and R₃are Br, Br, CO, CH₃, H and CH₃ respectively.
 18. The compound accordingto claim 1 in which X, Y, Z, R₁, R₂ and R₃ are Br, Br, CO, CH₃, CH₃ andC₆ H₅ respectively.
 19. The compound according to claim 1 in which X isBr, Y is Br, Z is CO, R₁ is CH₃ and R₂ and R₃ together are --C(CH₃)₂--(CH₂)₃ --C(CH₃)₂ respectively.
 20. The compound according to claim 1in which X, Y, Z, R₁, R₂ and R₃ are Br, Br, SO₂, CH₃, CH(CH₃)₂ andCH(CH₃)₂ respectively.
 21. The compound according to claim 1 in which X,Y, Z, R₁, R₂ and R₃ are H, H, CO, CH(CH₃)₂, CH₃ and CH₃ respectively.